17-44349172-C-G

Position:

• chr17-44349172-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002087.4(GRN):​c.8C>G​(p.Thr3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.554

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a signal_peptide (size 16) in uniprot entity GRN_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002087.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13726828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.8C>G	p.Thr3Ser	missense_variant	2/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.8C>G	p.Thr3Ser	missense_variant	2/13	1	NM_002087.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GRN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 3 of the GRN protein (p.Thr3Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.9
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T;.;T;.;T;.;.;T;T;T;T;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;.;.;.;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.052	T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.71	T;T;D;T;T;T;T;T;T;T;T;T;.
Polyphen		0.33	B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.34
MutPred		0.35		Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);
MVP		0.79
MPC		0.27
ClinPred		0.29	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375939802; hg19: chr17-42426540;